14-O-p-chlorobenzoylaconine and analgesic/anti-inflammatory agent containing the same

ABSTRACT

Analgesic/anti-inflammatory agent containing as active ingredient 14-O-p-chlorobenzoylaconine or a salt thereof. 14-O-p-chlorobenzoylaconine is a novel substance and a compound with high safety which shows an analgesic action on both inflammatory and non-inflammatory pains as well as an anti-inflammatory action. This compound can be used in the treatment of pain-causing diseases, both inflammatory and non-inflammatory, as well as in the treatment of inflammation.

TECHNICAL FIELD

This invention relates to novel compound 14-O-p-chlorobenzoylaconine ora salt thereof, as well as to a novel analgesic/anti-inflammatory agentcontaining the 14-O-p-chlorobenzoylaconine or salt thereof as activeingredient.

BACKGROUND ART

Aconitine alkaloids contained in the tuberous root of plants of thegenus Aconitium have already been reported to have a potent analgesicand anti-inflammatory activity. They, however, are supposed to show anarrow safety margin because of their high toxicity.

DISCLOSURE OF INVENTION

As a result of extensive studies in an attempt to develop novelaconitine alkaloid derivatives which are low in toxicity but maintainthe analgesic/anti-inflammatory activity that aconitine alkaloids have,we have already succeeded in providing "novel aconitine compounds andanalgesic/anti-inflammatory agent comprising the same" (Japanese patentapplication No. 2-283553). As a result of further studies, we have nowsucceeded in providing 14-O-p-chlorobenzoylaconine, a compound withexcellent pharmacological effects coupled with high safety.

Thus, the present invention provides a new compound,14-O-p-chlorobenzoylaconine of the formula: ##STR1## as well as a saltthereof. It also provides an analgesic/anti-inflammatory agentcontaining 14-O-p-chlorobenzoylaconine or a salt thereof as activeingredient together with an excipient.

The present invention will now be described in detail in the following.

The compound according to the invention of the formula (I) shown abovemay be prepared by using as starting material aconitine compoundsdescribed in the literature, such as aconitine, mesaconitine,jesaconitine, 14-O-benzoylaconine, 14-O-benzoylmesaconine and14-O-anisoylaconine shown below by the formulas (II) , (III), (IV) , (V), (VI) and (VII), respectively.

Where the compounds of the formulas (II), (IV), (V) and (VII) are usedas starting material, the compound of the formula (I) may be prepared bydeesterification into hydroxyl group of the substituent present at theposition 14 or 8 in the form of ester bond, through hydrolysis such asalkaline hydrolysis, followed by reaction with p-chlorobenzoyl chloridein an appropriate solvent such as pyridine.

Where the compounds of the formulas (III) and (VI) are used as startingmaterial, the compound of the formula (I) may be prepared by followingthe same steps as in the case where the compounds of the formulas (II),(IV), (V) and (VII) are used as starting material, i.e. deesterificationinto hydroxyl group of the substituent present at the position 14 or 8in the form of ester bond, through hydrolysis such as alkalinehydrolysis, followed by reaction with p-chlorobenzoyl chloride in anappropriate solvent such as pyridine, to give14-O-p-chlorobenzoylmesaconine; reacting the product with an appropriateoxidizing agent such as potassium permanganate in an appropriate solventsuch as acetone to give N-demethylated product; and reacting theN-demethylated product with an ethylating agent such as ethyl iodide.

    ______________________________________                                         ##STR2##                  (II)-(VII)                                                   R.sub.1 R.sub.2      R.sub.3                                        ______________________________________                                        II          Bz        CH.sub.2 CH.sub.3                                                                          OAc                                        III         Bz        CH.sub.3     OAc                                        IV          An        CH.sub.2 CH.sub.3                                                                          OAc                                        V           Bz        CH.sub.2 CH.sub.3                                                                          OH                                         VI          Bz        CH.sub.3     OH                                         VII         An        CH.sub.2 CH.sub.3                                                                          OH                                         ______________________________________                                         Bz: COC.sub.6 H.sub.5,                                                        An: COC.sub.6 H.sub.4 OCH.sub.3,                                              Ac: COCH.sub.3                                                           

The compound of the invention is a basic substance capable of formingsalts with inorganic acids such as hydrochloric acid, sulfuric acid andhydrobromic acid or with organic acids such as oxalic acid, succinicacid, tartaric acid, citric acid and ascorbic acid.

In the following will now be given working examples and experimentexamplesregarding the compound of the invention for further illustrationof the present invention Physicochemical parameters and analytical dataof the compound of the formula (I) prepared in these working examplesare given just after the description of the working examples.Pharmacological activity, toxicity etc. of compounds are shown in Tables1-6 mentioned below.

EXAMPLE 1

100 mg of aconitine was dissolved in 5 ml of 5% KOH in methanol. Thissolution was stirred at room temperature for 10 hours. The solvent wasevaporated off under reduced pressure and the resulting residue wasdissolved in 5 ml of ice water. This solution was chromatographed onAmberlite XAD2 (20 ml, product of Nippon Organo) which had been washedwith methanol and water in that order. After this column was washed bywater until the washings were free from alkalinity, it was eluted withmethanol (300 ml). The eluate was dried under reduced pressure to afford96 mg of residue containing aconine. This residue was dissolved in 2 mlofdistilled pyridine. To this solution, 0.06 ml of p-chlorobenzoylchloride was added and the mixture was stirred at -18° C. for 10minutes. After reaction, the reaction mixture was chromatographed on asilica gel (10 g) column, eluting with CHCl₃ (30 ml), 10% methanol inCHCl₃(30 ml), 15% methanol in CHCl₃ and 20% methanol in CHCl₃ inthatorder. The eluates with 10% methanol in CHCl₃ and 15% methanol inCHCl₃ were mixed and dried under reduced pressure. The residue wassubjected to column chromatography on silica gel (30 g), eluting withammonia-saturated chloroform and the so purified residue wasrecrystallized from acetone-hexane to afford 14-O-p-chlorobenzoylaconine(83 mg).

EXAMPLE 2

77 mg of 14-O-p-chlorobenzoylaconine was obtained in the same manner asin Example 1, except for the use of 100 mg of jesaconitine as asubstitute for aconitine in Example 1.

EXAMPLE 3

85 mg of 14-O-p-chlorobenzoylaconine was obtained in the same manner asin Example 1, except for the use of 100 mg of 14-O-benzoylaconine as asubstitute for aconitine in Example 1.

EXAMPLE 4

84 mg of 14-O-p-chlorobenzoylaconine was obtained in the same manner asin Example 1, except for the use of 100 mg of 14-O-anisoylaconine as asubstitute for aconitine in Example 1.

EXAMPLE 5

80 mg of 14-O-p-chlorobenzoylmesaconine was obtained in the same manneras in Example 1, except for the use of 100 mg of mesaconitine as asubstitutefor aconitine in Example 1. 80 mg of14-O-p-chlorobenzoylmesaconine were dissolved in 10 ml of acetone. Tothis solution, 4 ml of aqueous KMnO₄ solution (887 mg in 25 ml of water)and 0.7 ml of aqueous K₂ CO₃ solution (556 mg in 4.5 ml of water) wereadded and the mixture was stirred at room temperature for 30 minutes.The reaction mixture was concentrated under reduced pressure until theodor of acetone was no longer apparent. To the residual solution, 5 mlof 2N H₂ SO₄ and 3.5 ml of aqueous Na₂ S₂ O₃ solution (887 mg in 22 mlof water) were added and the mixture was washed with CH₂ Cl₂. Theaqueous layer was adjusted to pH 8-9 with Na₂ CO₃.This solution wasextracted with CH₂ Cl₂. The CH₂ Cl₂ layer was dried over Na₂ SO₄ andconcentrated to dryness in vacuo. The residue was subjected to columnchromatography on silica gel, eluting with 5% methanol inammonia-saturated CHCl₃ to affordde-N-methyl-14-O-p-chlorobenzoylmesaconine (58 mg). 58 mg ofde-N-methyl-14-O-p-chlorobenzoylmesaconine was dissolved in 2 ml of amixture of methanol and ether (1:1). To this solution, 65 mg of CaCO₃and0.5 ml of CH₃ CH₂ I were added and the mixture was refluxed for 2 hours.The reaction mixture was filtered off to remove insolubles andconcentrated to dryness under reduced pressure. The residue wassubjected to column chromatography on silica gel for separation andpurification, eluting with 5% methanol in ammonia-saturated CHCl₃ toafford 14-O-p-chlorobenzoylaconine (33 mg).

EXAMPLE 6

35 mg of 14-O-p-chlorobenzoylaconine was obtained in the same manner asin Example 5, except for the use of 14-O-benzoylmesaconine as asubstitute for mesaconitine in Example 5.

EXAMPLE 7

10 mg of 14-O-p-chlorobenzoylaconine was dissolved in 0.5 ml of ethanol.Tothis solution, 0.5 ml of an ethanolic solution of L(+)-tartaric acid(23 mgin 5 ml of ethanol) was added and the mixture was well mixed.Then, N₂gas was blowed against this solution to evaporate off theethanol in the solution to dryness. The residue was placed in adesiccator under reduced pressure to afford the tartaric acid salt of14-O-p-chlorobenzoylaconine (11.4 mg).

EXAMPLE 8

12.9 mg of the citric acid salt of 14-O-p-chlorobenzoylaconine wasobtainedin the same manner as in Example 7, except for the use of 32 mgof citric acid as a substitute for L(+)-tartaric acid in Example 7.

EXAMPLE 9

12 mg of the L(+)-ascorbic acid salt of 14-O-p-chlorobenzoylaconine wasobtained in the same manner as in Example 7, except for the use of 26 mgof L(+)-ascorbic acid as a substitute for L(+)-tartaric acid in Example7.

EXAMPLE 10

10.8 mg of the hydrobromic acid salt of 14-O-p-chlorobenzoylaconine wasobtained in the same manner as in Example 7, except for the use of 27 mgof hydrobromic acid as a substitute for L(+)-tartaric acid in Example 7.

Physicochemical parameters and analytical data of14-O-p-chlorobenzoylaconine

1) Analysis of IR spectra (KBr) IRν_(max) ^(KBr) : 3500, 1720 cm⁻¹.

2) Analysis of UV spectra (ethanol) UV λ_(max) ^(EtOH) (log ε) nm: 240(3.98).

3) Analysis of ¹ H--NMR spectra (CDCl₃) The following signals areshown(δ, ppm). 7.99 and 7.40 (each 2H, d, J=8.9 Hz, p-chlorobenzoyl group),4.97 (1H, d, J=5.4 Hz, C14-H), 3.71, 3.31, 3.30 and 3.26 (each 3H,s,OCH₃ at C1, C6, C16 and C18), 1.10 (3H, t, J=7.0 Hz, CH₃ of C₂ H₅ at thenitrogen atom).

4) Analysis of ¹³ C--NMR spectra (CDCl₃) The following signals are shown(δ, ppm). 165.3 (carbonyl of p-chlorobenzoyl group at C14), 139.6,131.1, 128.8 and 128.2 (p-chlorobenzoyl group), 90.7, 83.0, 82.4, 81.8,79.9, 78.5, 77.1, 74.6 and 71.6 (C16, C6, C1, C15, C14, C8, C18, C13 andC3), 60.8, 59.1, 58.0 and 55.7 (OCH₃ at C16, C18, C6 andC1), 48.9 (C₂ ofC₂ H₅ at the nitrogen atom), 13.0 (CH₃of C₂ H₅ at the nitrogen atom).

5) Analysis of Mass spectra m/z: 637, 639 (M⁺).

6) Property and solubility Colorless and odorless needles. m.p.221°-222° C. Soluble in ether, chloroform, benzene, methanol, ethanol,acetone, ethyl acetate, pyridine and dimethyl sulfoxide. Insoluble inhexane and water.

Examples of experiment with respect to the pharmacological property andacute toxicity of the compound shown in formula (I) mentioned above aredescribed below.

EXPERIMENT EXAMPLE 1 Measurement of Analgesic Activity by the AceticAcid-Induced Writhing Method

Male mice of the Std:ddY Strain (20-25 g), which were fasted for onenight before the initiation of the experiment, were used. Test compoundhardly soluble in water was used in 3% suspension in gum arabic. Testcompound taking a salt form was used in aqueous solution. 0.7% aceticacid in 0.9% physiological saline solution was injected i.p. (10 ml/kg)at 2 hours and 50 minutes after the test compound was administered p.o.After 10 minutes,the number of writhing movements was counted for aperiod of 10 minutes. The results are shown in Table 1. It wasdemonstrated in Table 1 that the compounds of this invention had adose-dependent potent analgesic activity.

EXPERIMENT EXAMPLE 2 Measurement of Analgesic Activity by thePhenylquinone-Induced Writhing Method

Male mice of the Std:ddY Strain (20-25 g), which were fasted for onenight before the initiation of the experiment, were used. Test compoundhardly soluble in water was used in 3% suspension in gum arabic. Testcompound taking a salt form was used in aqueous solution. 0.03%phenylquinone in 0.5% ethanol solution was injected i.p. (10 ml/kg) at 2hours and 55 minutes after the compound was administered p.o. After 5minutes, the number of writhings was counted for a period of 15 minutes.The results are shown in Table 2 described below. It was demonstrated inTable 2 that the compounds of this invention had a dose-dependent,potent analgesic activity.

EXPERIMENT EXAMPLE 3 Measurement of Analgesic Activity by theTail-Pressure Method

Male mice of the Std:ddY Strain (20-25 g), which were fasted for onenight before the initiation of the experiment, were used. Test compoundhardly soluble in water was used in 3% suspension in gum arabic. Testcompound taking a salt form was used in aqueous solution. Experimentswere made with a tail-pressure apparatus. Before the administration oftest compounds, the pain threshold was measured twice at intervals of 30minutes and those mice indicating a pain threshold of 30 to 80 mmHg wereselected and used. The pain threshold of each mouse was measured at 1, 3and 5 hours after test compounds were administered p.o. The results weredescribed as a percentage of the pain threshold after the treatment withtest compound relative to that before the treatment with test compound.The results are shown in Table 3. It was demonstrated in Table 3 thatthe compounds of this invention had a dose-dependent, potent analgesicactivity.

EXPERIMENT EXAMPLE 4 Measurement of Analgesic Activity by the Hot PlateMethod

Male mice of the Std:ddY Strain (20-25 g), which were fasted for onenight before the initiation of the experiment, were used. Test compoundhardly soluble in water was used in 3% suspension in gum arabic. Testcompound taking a salt form was used in aqueous solution. Mice wereplaced on a cyrindric hot plate (diameter: 22 cm, height: 11 cm) made ofcopper which was fixed in a water bath adjusted to 52° C. so that eachanimal's four paws came into contact with the plate and the time takento show the nociceptive response (jumping and licking) as an index ofpain was measured. Mice showing response times above 25 seconds wereexcluded from the experiment. The analgesic activity of the compound wasmeasured at 1, 3 and 5 hours after test compound was administered p.o.The results are shown in Table 4. It was demonstrated in Table 4 thatthe compound of thisinvention had a dose-dependent, potent analgesicactivity.

EXPERIMENT EXAMPLE 5 Measurement of Antiinflammatory Activity by theCarrageenin-Induced Hind Paw Edema

Male rats of the Wistar strain (5 weeks old, 120-130 g), which werefasted for one night before the initiation of the experiment, were used.One hourafter the oral administration of test compound, λ-carrageenin(1%) was injected s.c. under the plantar surface of the right hind paw.Thereafter, at one hour intervals for 6 hours, the volume of the paw wasmeasured using an apparatus therefor. The results were described as aswelling rate (%) calculated using the following equation:

    (R-L)×100/L=swelling rate (%)

R: the volume of the right hind paw

L: the volume of the left hind paw

The results are shown in Table 5. It was demonstrated in Table 5 thatthe compound of this invention had an inhibitory action against thecarrageenin-induced paw edema.

EXPERIMENT EXAMPLE 6 (ACUTE TOXICITY)

Male mice of the Std:ddY Strain (20-25 g), which were fasted for onenight before the initiation of the experiment, were used. Test compoundhardly soluble in water was used in 3% suspension in gum arabic. Testcompound taking a salt form was used in aqueous solution. The LD₅₀values werecalculated using the method of Litchfield-Wilcoxon from themortality during 72 hours after test compound was administered p.o. Theresults are shown in Table 6. As shown in Table 6, no death of mice wasseen even at the p.o. administration of 1000 mg/kg of the compound ofthis invention and the compound of this invention was thus found to bevery low in toxicity.

                  TABLE 1                                                         ______________________________________                                        Measurement of analgesic activity by the acetic                               acid-induced writhing method                                                                 Dose     The number of writhings                               Test compound  (mg/kg)  mean ± S.E.                                        ______________________________________                                        control         0       31.3 ± 3.5                                         8-deoxy-14-O-   3       24.1 ± 2.7                                         benzoylaconine 10       21.9 ± 2.6*                                                       30       17.8 ± 2.5**                                       14-O-p-         3       19.8 ± 2.5*                                        chlorobenzoylaconine                                                                         10       17.3 ± 2.4**                                                      30       12.9 ± 3.7**                                       14-O-p-         3       17.8 ± 2.5**                                       chlorobenzoylaconine                                                                         10       15.5 ± 2.3**                                       tartrate       30       10.7 ± 2.1**                                       ______________________________________                                        *P < 0.05,                                                                    **P < 0.01. n = 10.                                                       

                  TABLE 2                                                         ______________________________________                                        Measurement of analgesic activity by the                                      phenylquinone-induced writhing method                                                        Dose     The number of writhings                               Test compound  (mg/kg)  mean ± S.E.                                        ______________________________________                                        control         0       31.3 ± 3.2                                         8-deoxy-14-O-   3       27.1 ± 2.7                                         benzoylaconine 10       25.0 ± 3.0                                                        30       24.0 ± 2.3*                                        14-O-p-         3       20.1 ± 3.6*                                        chlorobenzoylaconine                                                                         10       17.3 ± 2.8**                                                      30       15.9 ± 3.5**                                       14-O-p-         3       21.1 ± 2.4**                                       chlorobenzoylaconine                                                                         10       18.3 ± 2.2**                                       tartrate       30       15.7 ± 2.7**                                       ______________________________________                                        *P < 0.05,                                                                    **P < 0.01. n = 8˜ 10.                                              

                                      TABLE 3                                     __________________________________________________________________________    Measurement of analgesic activity by the tail-pressure method                               Dose Pain threshold (%, mean ± S.E.).sup.1)                  Test compound (mg/kg)                                                                            1      3       5 (h)                                       __________________________________________________________________________    control        0   90.7 ± 2.9                                                                        95.2 ± 2.9                                                                         92.2 ± 2.8                               8-deoxy-14-O-benzoylaconine                                                                 100  101.8 ± 14.1                                                                      100.2 ± 7.2                                                                        105.6 ± 9.2                                            300  115.6 ± 17.0*                                                                     116.2 ± 12.0*                                                                      110.2 ± 7.0*                             14-O-p-chlorobenzoylaconine                                                                 100  100.4 ± 2.5                                                                       129.6 ± 10.3**                                                                     108.0 ± 6.0*                                           300  120.0 ± 7.3**                                                                     182.0 ± 21.7**                                                                      166.0 ± 20.1**                          14-O-p-chlorobenzoylaconine                                                                 100  102.6 ± 3.4*                                                                      141.1 ± 8.3**                                                                       128.0 ± 4.9**                           tartrate      300  147.0 ± 7.8**                                                                     240.4 ± 25.0**                                                                      202.9 ± 19.7**                          __________________________________________________________________________    *P < 0.05,                                                                    **P < 0.01. n = 6˜ 34.                                                   .sup.1) Percentage of the posttreatment relative to the pretreatment pain     threshold.                                                               

                                      TABLE 4                                     __________________________________________________________________________    Measurement of analgesic activity by the hot plate method                                   Dose Pain threshold (s, mean ± S.E.)                         Test compound (mg/kg)                                                                            1      3       5 (h)                                       __________________________________________________________________________    control        0   14.3 ± 0.8                                                                        16.6 ± 0.9                                                                         18.9 ± 1.4                               8-deoxy-14-O-benzoylaconine                                                                 100  17.3 ± 1.7                                                                        17.9 ± 2.1                                                                         18.9 ± 1.7                                             300  18.6 ± 1.6*                                                                        24.0 ± 2.3**                                                                      19.6 ± 2.0                               14-O-p-chlorobenzoylaconine                                                                 100   21.6 ± 2.2**                                                                     21.6 ± 2.0*                                                                         27.6 ± 0.9**                                          300   22.2 ± 1.5**                                                                      38.4 ± 3.3**                                                                      24.0 ± 1.6*                              14-O-p-chlorobenzoylaconine                                                                 100  17.3 ± 2.2*                                                                        26.7 ± 3.2**                                                                      24.7 ± 2.1*                              tartrate      300  18.7 ± 1.7*                                                                        42.5 ± 11.0**                                                                     25.7 ± 2.7*                              __________________________________________________________________________    *P < 0.05,                                                                    **P < 0.01. n = 7˜ 14.                                              

                                      TABLE 5                                     __________________________________________________________________________    Measurement of the carrageenin-induced paw edema (antiinflammatory            activity)                                                                             Dose Swelling rate (%, mean ± S.E.)                                Test compound                                                                         (mg/kg)                                                                            1     2      3     4      5      6 (h)                           __________________________________________________________________________    control  0   28.6 ± 5.4                                                                       38.9 ± 3.3                                                                        73.5 ± 7.6                                                                       75.9 ± 4.6                                                                        80.0 ± 2.1                                                                        81.2 ± 6.7                   8-deoxy-14-O-                                                                         100  24.8 ± 9.2                                                                       36.3 ± 6.3                                                                        59.8 ± 6.3                                                                       63.5 ± 1.0*                                                                       70.3 ± 3.9*                                                                       72.2 ± 6.0                   benzoylaconine                                                                14-O-p-chloro-                                                                        100  22.4 ± 8.0                                                                        28.0 ± 2.4*                                                                      51.0 ± 2.8*                                                                      58.6 ± 2.4*                                                                       66.8 ± 3.7**                                                                      72.9 ± 5.3                   benzoylaconine                                                                14-O-p-chloro-                                                                        100  16.0 ± 3.6                                                                       31.5 ± 3.1                                                                        47.3 ± 7.4*                                                                       56.1 ± 2.0**                                                                     49.6 ± 5.0**                                                                       57.6 ± 9.0*                 benzoylaconine                                                                tartrate                                                                      __________________________________________________________________________    *P < 0.05,                                                                    **P < 0.01. n = 6˜ 8.                                               

                  TABLE 6                                                         ______________________________________                                        Toxicity                                                                      Test compound          LD.sub.50 (mg/kg)                                      ______________________________________                                        8-deoxy-14-O-benzoylaconine                                                                          100<                                                   14-O-p-chlorobenzoylaconine                                                                         1000<                                                   14-O-p-chlorobenzoylaconine tartrate                                                                1000<                                                   ______________________________________                                    

The aforementioned demonstrates that the compound of the formula (I) hasananalgesic/anti-inflammatory activity as well as a low toxicity withthe LD₅₀ being not lower than 1,000 mg/kg.

The dose of the compound of the formula (I) for clinical use asanalgesic/anti-inflammatory agent according to the invention ispreferably1-1,000 mg/day for adults. The agent according to the presentinvention is presented for actual application after formed into desireddosage forms byconventional methods using customarily used carriers orexcipients. Wherever appropriate or necessary, the compound of thepresent invention may be used in the form of a salt thereof forachieving its pharmaceuticaleffect or facilitating the preparation ofdosage forms.

Oral preparations such as tablets, powders, granules and capsules maycontain conventional excipients such as calcium carbonate, magnesiumcarbonate, calcium phosphate, corn starch, potato starch, sugar,lactose, talc, magnesium stearate and gum arabic. Tablets may be coatedby conventional methods. Oral liquid preparations may be aqueous or oilysuspensions, solutions, syrups, elixirs etc.

For injectable preparations, the compound of the formula (I) may be usedinthe form of a salt thereof, and preferably reconstituted upon use.Such preparations may contain different adjuvants such as suspending,stabilizing or dispersing agents. They may contain sterilized distilledwater, refined oils such as peanut oil and corn oil, non-aqueoussolvents,polyethylene glycol, polypropylene glycol, etc.

Preparations for rectal administration are presented in the form ofcompositions for suppository and may contain pharmaceutical carrierswell known in the art such as polyethylene glycol, lanolin and coconutoil.

Preparations for topical application are presented in the form ofcompositions for ointment, plaster or poultice and may containpharmaceutical carriers well known in the art such as vaseline,paraffin, hydrous lanolin, plastibase, kaolin, bentonite, talc, aluminumsilicate, propylene glycol, sorbitol, hydrophilic petrolatum, macrogols,wax, resin,purified lanolin, gum, glycerin, gelatin, polyacrylic acid,polyacrylic acid salt, polyvinyl alcohol, polyvinyl pyrrolidone andpolyethylene oxide.

I claim:
 1. 14-O-p-chlorobenzoylaconine of the formula (I) ##STR3## or apharmaceutically acceptable salt thereof.
 2. Ananalgesic/anti-inflammatory composition comprising as the activeingredient an effective amount of 14-o-p-chlorobenzoylaconine or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable excipient or adjuvant.